The present invention relates to metformin salts, processes for preparing such salts, intermediates used in the preparation of such salts, processes for preparing such intermediates, pharmaceutical compositions comprising such salts and methods of treating diabetes in mammals comprising administering to said mammals said salts or said compositions.
Metformin, also known by other names including N,N-dimethylimidodicarbonimidic diamide and 1,1-dimethylbiguanide, is a known compound and it is disclosed in J. Chem. Soc., 1922, 121, 1790. The compound and its preparation and use are also disclosed, for example, in U.S. Pat. No. 3,174,901. Metformin is orally effective in the treatment of type 2 diabetes. Metformin is currently marketed in the United States in the form of its hydrochloride salt as an anti-hyperglycemic agent (formula I). Metformin hydrochloride can be purchased commercially and can also be prepared, for example, as disclosed in J. Chem. Soc., 1922, 121, 1790. It is postulated that metformin decreases hepatic glucose production and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin hydrochloride is approved by the United States Food & Drug Administration for the therapeutic treatment of diabetes and it is widely regarded as the drug of choice for most patients with type 2 diabetes.
U.S. Pat. No. 7,973,073 B2 (Mylari et al) describes use of metformin R-(+) lipoate as being useful for treating diabetes or diabetic complications.
According to United Kingdom Perspective Diabetes Study (UKPDS) (Clarke et al. Diabetologia, 2005, 48, 868-877), metformin therapy was cost-saving and increased quality-adjusted life expectancy. In the UKPDS, overweight and obese patients randomized to initial therapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with Type 2 diabetes.
Prediabetes is a syndrome. Many patients with type 2 diabetes and with a prediabetic condition known as metabolic syndrome suffer from a variety of lipid disorders including elevated triglycerides. The body uses triglycerides to store fat but high (>200 mg/dl) and very high (>500 mg/dl) triglycerides are associated with atherosclerosis which increases the patients risk of heart attack and stroke.
Incipient diabetes with impaired glucose tolerance is another prediabetic condition. Overall, type 2 diabetes and incipient diabetes with impaired glucose tolerance, are intimately intertwined with obesity, hyperlipidemia, including hypertriglyceridemia, and cardiovascular complications including arrhythmia, cardiomyopathy, myocardial infarction, stroke and heart failure. Clinically, pre-diabetes means that blood sugar level is higher than normal, but it's not yet increased enough to be classified as type 2 diabetes. Still, without intervention, prediabetes is likely to become type 2 diabetes over time
It is a matter of great concern that many patients are known to develop resistance to metformin over time. According to Shoelson et al, in The Journal of Clinical Investigation, 2006, 116, 1793-1801 increased levels of markers and mediators of inflammation correlate with incident type 2 diabetes. Subsequently, A. B. Goldfine et al, in Annals of Internal Medicine, 2010, 152, 346-357 and references cited therein, have shown that the compound of formula III, also known as salsalate, lowers blood glucose, HbA1c levels, triglycerides, free fatty acid and C-reactive protein in patients with type 2 diabetes. Also, salsalate was said to improve glucose utilization and was said to increase circulating insulin. Furthermore it was said to increase adiponectin concentrations. Unlike any other known antidiabetic, salsalate is thought to target the inflammation component of diabetes. Thus salsalate may provide a new avenue for treatment. Very recently, a new aspect of salsalate has come to light. According to Nixon et al, Diabetes Publish Ahead of Print, published online Feb. 22, 2012, the anti-inflammatory agent salsalate alters glucocorticoid metabolism in mice and humans in a pattern that differs between liver and subcutaneous adipose tissue. Down regulation of intra-adipose 11β-hydroxysteroid dehydrogenase-1 may contribute to the insulin sensitizing effect of salicylates. Also, Shoelson et al (US 2011/0021468 A1, Jan. 27, 2011) have described the use of salsalate in atherosclerotic cardiovascular disease. Salsalate is thought to be a prodrug of salicylic acid (formula II). Similarly the compound of the formula IV and the compound of the formula V can also be regarded as prodrugs of salsalate and salicylic acid. It is well known in the art that highly water soluble medicinal preparations, when administered orally, result in efficient absorption of such preparations from the gastrointestinal tract into systemic circulation. Another hallmark of such preparations is the rate at which they are absorbed into systemic circulation resulting in high concentration of the active agent or agents in the blood. According to The Merck Index, Eleventh Edition, 1 g. of salicylic acid is soluble in 460 mL of water (i.e. water solubility is 2.17 mg/mL) and salsalate is practically insoluble in water. The salts of the present invention are markedly more water soluble to provide concomitant delivery of both metformin and salicylic acid and its congeners, thus providing a dual action in targeting both hepatic glucose production and inflammation aspects of type 2 diabetes in patients with type 2 diabetes. Furthermore, the new salts would offer a patient friendly dosage form of two active therapies in a fixed dosage combination with increased reliability for daily patient compliance. Juvisync, recently approved by the United States Food and Drug Administration, is a contemporary example of a fixed combination of two widely used drugs for reliability of usage and patient convenience (FDA News Release. Oct. 7, 2011).
